The success of cisplatin [cis-diamminedichloroplatinum(II)] to treat cancer has stimulated scientists to develop cisplatin analogues [Wong, E. et al. Chem. Rev. 1999, 99, 2451] and other classes of metal-based drug [Sadler, P. J. et al. J. Am. Chem. Soc. 2002, 124, 3064; Sadler, P. J. Curr. Opin. Chem. Biol. 2008, 12, 197]. A variety of gold(I) and gold(III) compounds have been demonstrated to overcome the cisplatin-related resistance and induce DNA-independent apoptosis [Berners-Price, S. J. (2011) Gold-Based Therapeutic Agents: A New Perspective, in Bioinorganic Medicinal Chemistry (ed E. Alessio), Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany. doi:10.1002/9783527633104.ch7]. Nevertheless, one of the major challenges to clinically develop gold compounds as anti-cancer agents is to overcome the stability problem. Various reported gold(III) compounds are unstable under physiological conditions especially in the presence of biological reductants (e.g., glutathione). On the other hand, numerous reported gold(I) compounds would undergo rapid ligand exchanging reaction with physiological thiols (e.g., free cysteine in serum albumin) before reaching solid tumor tissues. As a consequence, the gold(I) compounds, such as auranofin, were found to be only effective to leukemia but display no effects to other solid tumors [Christopher et al. Cancer Res. 1985, 45, 32].
In literature, several physiological stable mono-nuclear gold(I) compounds which are relatively stable against ligand exchanging reactions with physiological thiols have been reported. One of these examples, [Au(dppe)2]Cl (wherein dppe=1,2-bis(diphenylphosphino)ethane), which is a phosphine-containing gold(I) compound, was found to be inert to physiological thiols and can effectively inhibit tumor growth in vivo [Berners-Price, S. J. et al. Cancer Res. 1986, 46, 5486]. Yet, this compound displayed severe side effects and toxicity to lung, heart and liver, as a result of mitochondria dysfunction [Berners-Price, S. J.; Filipovska, A. Metallomics 2011, 3, 863]. In a recent study, another anti-cancer gold(I) compound [Au(d2pypp)2]Cl (wherein d2pypp=1,3-bis(dipyridin-2-ylphosphino)propane) has been developed. This compound is relatively less lipophilic and has an increased reactivity towards thiol and may target to mitochondria thioredoxin reductase (TrxR). A cell-based study revealed that [Au(d2pypp)2]Cl could selectively induce apoptosis in cancer cells but not in normal cells [Berners-Price, S. J. et al. Dalton Trans 2007, 4943]. We reckon that the anti-cancer activity as well as its bio-availability of this compound could be further enhanced by appropriate structural modification of the phosphine ligand. Nevertheless, there remains a formidable challenge for chemists to strategically modify this phosphine-containing compound, since modification on phosphine is rather complicated and it commonly requires Schlenk techniques and low-temperature (−40° C.) synthesis.
A series of binuclear gold(I) compounds [Au2(dcpm)2]2+ (wherein dcpm=bis(dicyclohexylphosphanyl)methane) were found to be highly luminescent as a result from the Au(I) . . . Au(I) attraction (Che, C.-M. et al. Angew. Chem. Int. Ed. 1999, 38, 2783.; Che, C.-M. et al. J. Am. Chem. Soc. 1999, 121, 4799). Some binuclear gold(I) compounds such as [Au2(dppm)Cl2] (wherein dppm=bis(diphenylphosphino)methane) were found to induce autophagy in cancer cells (Che, C.-M. et al. Chem. Commun. 2011, 47, 9318). In addition to the phosphine ligands, N-heterocyclic carbene (NHC) and dithiocarbamate ligands have been employed to stabilize various kinds of metal ions in preparing metal-based anti-cancer agents (Che, C.-M. et al. Chem. Commun. 2010, 46, 3893; Che, C.-M. et al. Chem. Sci. 2011, 2, 728; Berners-Price, S. J.; Filipovska, A. et al. J. Am. Chem. Soc. 2008, 130, 12570; Fregona, D. et al. Int. J. Cancer. 2011, 129, 487). With these successful anti-cancer precedents, we believe that gold(I) compounds containing two different types of bidentate ligands including the diphosphine and dicarbene/dithiocarbamate would have potent prospects for the treatment of cancers.